22q13 Deletion Syndrome - Etiology

Etiology

The deletion affects the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases), from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the deletion is variable and can go from 130kbp (130,000 base pairs) to 9Mbp (9,000,000 base pairs). While some clinical signs correlate with the size of the deletion, the main traits of the syndrome appear to be independent of the deletion size, and only related to the presence of the Shank3 gene. The haploinsufficiency of Shank3 is thought to be the responsible for the neurological deficits of the syndrome.

The proteins encoded by the Shank genes assemble glutamate receptors with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density. They are important for the formation and stabilisation of synapses:

• Experimentally induced expression of Shank3 has been shown to be sufficient to induce functional dendritic spines in aspiny cerebellar neurons.
• Neural network activity up- or down regulates large groups of postsynaptic proteins through ubiquitin-mediated protein degradation. Shank proteins were identified as one of the few postsynaptic density proteins that can be degraded by ubiquitination

In 2006, a group led by Thomas Bourgeron from the Pasteur Institute in France, found anomalies of the 22q13 locus in five children with diagnosis of autism and Asperger syndrome. While the absence of the Shank3 gene was found in children with the typical characteristics of the Phelan-McDermid syndrome, its duplication was found in one child diagnosed with Asperger syndrome, a type of high-functioning autism.

Van Bokhoven et al. (1997) have also assigned the WNT7B gene to 22q13. Wnt7b acts through Dvl1 to the regulation of dendritic development. found that its overexpression resulted in increased dendritic branching in cultured mouse hippocampal neurons. Knockout mice for Dvl1 are viable, fertile and structurally normal, but show reduced social interaction and abnormal sleeping patterns. Heterozygous knockout mice for Shank3 are viable. Bangash et al. created a gain-of-function transgenic mouse bearing a deletion at the C terminus of Shank3 that mimics clinical mutations and define a biochemical pathway linking mutant Shank3 to the proteasomal degradation of Shank3 and NMDA type glutamate receptors subunit NR1. PMID 21565394 The heterozygous mutant mice display autism-like behavioral deficits and also exhibit schizophrenia-like phenotypes, consistent with altered glutamate receptor function. Consistent with this, the mice have deficits in NMDA LTP, LTD and enhanced mGluR LTD similar to Fragile-X. These results suggest that NMDA receptor degradation could be a shared feature of both Autism and Schizophrenia. Homozygous PDZ domain knockout mice from another lab also display autistic-like behaviours and striatal dysfunction.